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Variable Clinical Presentation of Glycogen Storage Disease Type IV: from Severe Hepatosplenomegaly to Cardiac Insufficiency

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Variable Clinical Presentation of Glycogen Storage Disease Type IV: from Severe Hepatosplenomegaly to Cardiac Insufficiency Letter to the Editor Variable clinical presentation of glycogen storage disease type IV: from severe hepatosplenomegaly to cardiac insufficiency. Some discrepancies in genetic and biochemical abnormalities Edyta Szymańska1, Sylwia Szymańska2, Grażyna Truszkowska3, Elżbieta Ciara4, Maciej Pronicki2, Yoon S. Shin5, Teodor Podskarbi6, Alina Kępka7, Mateusz Śpiewak8, Rafał Płoski9, Zofia T. Bilińska10, Dariusz Rokicki1 1Department of Pediatrics, Nutrition and Metabolic Disorders, the Children’s Corresponding author: Memorial Health Institute, Warsaw, Poland Dariusz Rokicki MD, PhD 2Department of Pathology, the Children’s Memorial Health Institute, Warsaw, Poland Department of Pediatrics, 3Department of Medical Biology, Molecular Biology Laboratory, Institute Nutrition and of Cardiology, Warsaw, Poland Metabolic Disorders 4Department of Medical Genetics, the Children’s Memorial Health Institute, Warsaw, Children’s Memorial Poland Health Institute 5University Children’s Hospital and Molecular Genetics and Metabolism Laboratory, Al. Dzieci Polskich 20 Munich, Germany 04-730 Warsaw, Poland 6Molecular Genetics and Metabolism Laboratory, Munich, Germany Phone: +48 22 815 75 45 7Department of Biochemistry, Radioimmunology and Experimental Medicine, E-mail: [email protected] the Children’s Memorial Health Institute, Warsaw, Poland 8Cardiac Magnetic Resonance Unit, Institute of Cardiology, Warsaw, Poland 9Department of Medical Genetics, Centre of Biostructure, Medical University of Warsaw, Warsaw, Poland 10Unit for Screening Studies in Inherited Cardiovascular Diseases, Institute of Cardiology, Warsaw, Poland Submitted: 19 February 2017 Accepted: 26 June 2017 Arch Med Sci 2018; 14, 1: 237–247 DOI: https://doi.org/10.5114/aoms.2018.72246 Copyright © 2017 Termedia & Banach Glycogen storage disease (GSD) type IV (Andersen’s disease, amy- lopectinosis, polyglucosan body disease) is a rare inherited disorder of carbohydrate metabolism. The disease is caused by autosomal recessive mutations in the GBE1 gene (OMIM 607839), which leads to glycogen branching enzyme (GBE) deficiency. This is a critical enzyme in the pro- duction of both muscle and liver glycogen. Due to its decreased activity, abnormal long branched molecules of low solubility are formed. These deposits lead to glycogen precipitation in the liver, and subsequently build up in the body tissue, especially the heart and liver. The severity of the disease varies according to the amount of enzyme produced. In adults, the activity of GBE is higher and symptoms do not appear until later in life [1]. Therefore, clinical manifestations of GSD IV consist of different sub- types with variable ages of onset, severity, and clinical features. The fatal perinatal neuromuscular subtype, which presents in utero with decreased fetal movements, polyhydramnios, and fetal hydrops, and con- genital neuromuscular subtype beginning in the newborn period with profound hypotonia, respiratory distress, and dilated cardiomyopathy, both result in death in the neonatal period. The classic progressive he- patic subtype presents with rapidly developing failure to thrive following birth. Clinical manifestations include hepatomegaly, liver dysfunction, E, Szymańska, S. Szymańska, G. Truszkowska, E. Ciara, M. Pronicki, Y.S. Shin, T. Podskarbi, A. Kępka, M. Śpiewak, R. Płoski, Z.T. Bilińska, D. Rokicki and progressive liver cirrhosis, as well as hypoto- ous parents of Polish origin. The pregnancy was nia, and cardiomyopathy. In this case, death due not complicated, but slow physical development to liver failure usually occurs by the age of 5 years was observed from the 28th gestation week. La- unless liver transplantation (LTx) is performed. bor was complicated with oligoamnios, and pelvic The non-progressive hepatic subtype presents longitudinal lie. Apgar scores were 6–7–8 respec- with hepatomegaly, liver dysfunction, myopathy, tively. Psychomotor development delay and poor and hypotonia. However, individuals with this type body mass gain were observed from her perina- usually do not show progression of liver disease, tal period. The child presented with mild hypo- and may not even have cardiac, skeletal muscle, or tonia, dysplasia of the hip, and pes equine. From neurologic involvement. The childhood neuromus- 5 weeks of age elevated liver enzymes, cholesta- cular subtype, which is the rarest one, has most sis (bilirubin: total 32.7 μmol/l, direct 14.3 μmol/l) variable course. Its onset ranges from the second and increased cholesterol and triglyceride levels life decade with a mild disease course to a more were found and persisted. At the age of 9 months severe, progressive course resulting in death in the girl remained microsomic (body mass – 2.0 SD, the third decade [2, 3]. height – 3.48 SD), her psycho-motor development The disease diagnosis and management is thus was markedly delayed, and liver and spleen were multidisciplinary, and should include specialists in enlarged. Lysosomal storage diseases suspected metabolic disorders, hepatology, neurology, and due to very high serum chitotriosidase activity nutrition, as well as in medical or biological ge- (5000 nmol/ml/h, ref. < 150) were excluded by en- netics. zymatic testing. During subsequent months por- We report three cases of Polish patients with tal hypertension, muscle hypotonia of lower limbs, mutations in the GBE1 gene with various clinical and hypertrophic cardiomyopathy developed. The courses of their disease each. girl required endoscopic intervention three times Patient 1: The girl was born in 2006 as a former due to the massive bleeding from esophagal vari- 2.4 kg term infant to healthy, non-consanguine- ces performed at the age of 19 months. A B C D Figure 1. Histological findings in patients 1 and 2.A – Patient 1: explanted liver showing cirrhosis and extensive amylopectin deposits. PAS stain. Original magnification 200×.B – Patient 1: Autopsy, heart muscle with numerous intrasarcoplasmic PAS-positive deposits. PAS stain. Original magnification 200×.C – Patient 1: Autopsy, brain ner- vous tissue with numerous globular PAS-positive deposits located in the white matter. Original magnification 400×. D – Patient 2: Core needle liver biopsy. Intrahepatocytic amylopectin deposits. PAS stain. Original magnification 200× 238 Arch Med Sci 1, January / 2018 Variable clinical presentation of glycogen storage disease type IV: from severe hepatosplenomegaly to cardiac insufficiency. Some discrepancies in genetic and biochemical abnormalities Liver transplantation was performed at the Autopsy revealed: (1) heart muscle and peri- age of 22 months. Complete micronodular cir- cardial involvement with extensive intracytoplas- rhosis, sparse diffuse lymphocytic infiltration mic PAS-positive deposits in cardiomyocytes (Fig- and presence of large or granular PAS-positive ure 1 B) and subpericardial macrophages, and intracytoplasmic inclusions located in numerous (2) diffuse central nervous system damage caused hepatocytes were found in the liver explant (Fig - by widespread deposition of numerous small glob- ure 1 A). In routine hematoxylin and eosin stain ular PAS-positive deposits. Their location included inclusions displayed basophilic or amphophilic the cerebral and cerebellar cortex as well as white staining characteristics. Transmission electron matter (Figure 1 C). microscopy of the liver revealed aggregates con- Patient 2: The boy was born in 1999 as a for- sistent with amylopectin deposition. Enzymatic mer 4.14 kg term infant of a 3rd uncomplicated study showed brancher deficiency both in leuko- pregnancy to healthy, non-consanguineous par- cytes and in the liver but normal activity in fibro- ents of Polish origin. The labor was also not com- blasts (Table I). plicated and the Apgar score was 10. His psycho- After LTx the girl’s hepatic function improved, motor development was good. At 9 months of age her mental development was good, but her mo- mild hepatomegaly and hypertransaminasemia tor skills were still greatly delayed; she was hypo- (ASP 319 U/l, ALT 263 U/l) were found on a rou- tonic, presented with muscle atrophy and did not tine health maintenance visit. A complete gastro- walk. Her body mass was at the 50th percentile, logic and metabolic work-up was performed at and height at the 3rd percentile. At 6.5 years of the age of 13 months and revealed deficiency of age, the girl was admitted to the hospital due to branching enzyme (Table I), which indicated the symptoms of sepsis with pulmonary abscess and GSD type IV. Brancher activity in leukocytes of the severe breathing difficulties. She died after a few patient’s parents was at the lower limit of the nor- weeks of intensive medical care. mal range. Liver core needle biopsy performed at Table I. Activities of enzymes involved in synthesis and degradation of glycogen and glycogen amount in morphotic elements of the blood in three patients with molecularly confirmed GSD type IV Activity* Patient 1 Patient 2 Patient 3 Liver: Brancher (ref. 0.3–3.0) 0.0 0.0 – Debrancher (ref. 0.17–0.72) – 0.21 – Fibroblasts: Brancher (ref. 0.5–3.0) 1.7 0.16 0.30 (c 1.73; 2.31) (c 1.5; 0.98) (c 0.99) Leukocytes: Brancher (ref. 0.22–0.81) 0.11 0.04 0.20 (M 0.28; F 0.20) (M 0.20; F 0.16; B 0.16) Debrancher (ref. 26.8–105): Phosphorylase a with AMP (ref. 1.0–3.2) – 1.2 2.1 Phosphorylase a without AMP (ref. 0.46–2.2) – – 1.24 – FBP-1,6-ase (ref. 0.89–15.9) – 4.6 – Erythrocytes – Glycogen (ref. 5.7–135) – 16.7 112 Phosphorylase b kinase (ref. 8.6–45.9) Activity* Patient 1 Patient 2 Patient 3 Liver M – mother, F – father, B – brother, c – control, FBP-1,6-ase – fructose-1,6-biphosphatase; *Units brancher – µmol Pi/min/mg protein, debrancher in liver (leukocytes) – µmol glucose/mg protein/hour (nmol glucose/mg protein/h), phosphorylase a (with, without ± AMP) – µmol Pi/h/mg protein, glycogen – µg/g hemoglobin, phosphorylase b kinase – µmol Pi/min/g hemoglobin. FBP-1,6-ase – µmol/min/mg protein. **Normal ranges of brancher in Laboratory in Munich: leukocytes 0.22–0.81; fibroblasts 0.5–3.0; liver 0.3–3. Arch Med Sci 1, January / 2018 239 E, Szymańska, S. Szymańska, G. Truszkowska, E.
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